VCV000056304.13 - ClinVar

NM_001378615.1(CC2D2A):c.3341C>T (p.Thr1114Met)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic
Pathogenic (2); Likely pathogenic (2)

4 out of 6 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001378615.1(CC2D2A):c.3341C>T (p.Thr1114Met)

Variation ID: 56304 Accession: VCV000056304.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4p15.32 4: 15567729 (GRCh38) [ NCBI UCSC ] 4: 15569352 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 24, 2013	May 3, 2026	Jan 26, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_001378615.1:c.3341C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001365544.1:p.Thr1114Met	missense
NM_001080522.2:c.3341C>T	NP_001073991.2:p.Thr1114Met	missense
NM_001378617.1:c.3194C>T	NP_001365546.1:p.Thr1065Met	missense
NC_000004.12:g.15567729C>T
NC_000004.11:g.15569352C>T
NG_013035.1:g.102864C>T
LRG_697:g.102864C>T
LRG_697t1:c.3341C>T	LRG_697p1:p.Thr1114Met
	Q9P2K1:p.Thr1114Met

... more HGVS ... less HGVS

Protein change

T1114M, T1065M

Other names

Canonical SPDI

NC_000004.12:15567728:C:T

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00004

Exome Aggregation Consortium (ExAC) 0.00005

Links

ClinGen: CA144225 UniProtKB: Q9P2K1#VAR_062293 dbSNP: rs386833752 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CC2D2A		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	2127	2458

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Meckel syndrome, type 6	Likely pathogenic (1)	no assertion criteria provided	-	RCV000049716.2
Joubert syndrome 9	Pathogenic (1)	criteria provided, single submitter	Feb 23, 2015	RCV000201581.1
Polydactyly	no classifications from unflagged records (1)	no classifications from unflagged records	Mar 26, 2024	RCV001007916.2
not provided	Likely pathogenic (1)	criteria provided, single submitter	Dec 16, 2025	RCV001539860.4
Joubert syndrome Meckel-Gruber syndrome	Pathogenic (1)	criteria provided, single submitter	Jan 26, 2026	RCV002514252.5
COACH syndrome 2 Joubert syndrome 9 Meckel syndrome, type 6 Retinitis pigmentosa 93	Likely pathogenic (1)	criteria provided, single submitter	Jan 27, 2025	RCV006684521.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Jan 27, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	COACH syndrome 2 Joubert syndrome 9 Meckel syndrome, type 6 Retinitis pigmentosa 93 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. (Autosomal recessive inheritance)	First Genomix Gene Laboratory, Genetic Diagnostics Department Accession: SCV007580504.1 First in ClinVar: May 03, 2026 Last updated: May 03, 2026	Comment: show As part of Carrier Screening testing performed at First Genomix, this variant was identified in a heterozygous state in a patient who is not affected with this condition. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no Number of individuals with the variant: 1

Pathogenic (Feb 23, 2015) C Contributing to aggregate classification	criteria provided, single submitter (Bachmann-Gagescu et al. (J Med Genet. 2015))	Joubert syndrome 9	UW Hindbrain Malformation Research Program, University of Washington Additional submitter: University of Washington Center for Mendelian Genomics, University of Washington Accession: SCV000256360.1 First in ClinVar: Nov 09, 2015 Last updated: Nov 09, 2015	Publications: PubMed (1) PubMed: 26092869 Observation: 1 Collection method: research Allele origin: unknown Affected status: yes Observation 1 Collection method: research Allele origin: unknown Affected status: yes

Likely pathogenic (Dec 16, 2025) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV001757680.3 First in ClinVar: Jul 24, 2021 Last updated: Jan 11, 2026	Comment: show Reported in a patient with Meckel syndrome who also harbored a second CC2D2A variant (PMID: 19466712); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19777577, 38036193, 26092869, 34234304, 31964843, 19466712) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Jan 26, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Joubert syndrome Meckel-Gruber syndrome Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003287032.4 First in ClinVar: Feb 07, 2023 Last updated: Feb 23, 2026	Publications: PubMed (3) PubMed: 19466712‚ 19777577‚ 26092869 Comment: show This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1114 of the CC2D2A protein (p.Thr1114Met). This variant is present in population databases (rs386833752, gnomAD 0.01%). This missense change has been observed in individual(s) with CC2D2A-related conditions (PMID: 19466712, 19777577, 26092869). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56304). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CC2D2A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	Meckel syndrome, type 6	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) Accession: SCV000082123.2 First in ClinVar: Jul 24, 2013 Last updated: Jun 08, 2025 Comment: FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference	Comment: show Converted during submission from probable-pathogenic to Likely pathogenic. (less) Observation: 1 Collection method: not provided Allele origin: unknown Affected status: not provided Observation 1 Collection method: not provided Allele origin: unknown Affected status: not provided

Uncertain significance (Jul 26, 2018) N Not contributing to aggregate classification	Flagged submission flagged submission (ACMG Guidelines, 2015) Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Polydactyly (Autosomal recessive inheritance)	Genomic Medicine Lab, University of California San Francisco Study: CSER Accession: SCV001167625.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Observation: 1 Collection method: clinical testing Allele origin: paternal Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: paternal Affected status: unknown Test name: Exome sequencing Secondary finding: no Platform type: next-gen sequencing Platform name: HiSeq

Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

Reported in a patient with Meckel syndrome who also harbored a second CC2D2A variant (PMID: 19466712); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19777577, 38036193, 26092869, 34234304, 31964843, 19466712)

Comment:

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1114 of the CC2D2A protein (p.Thr1114Met). This variant is present in population databases (rs386833752, gnomAD 0.01%). This missense change has been observed in individual(s) with CC2D2A-related conditions (PMID: 19466712, 19777577, 26092869). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56304). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CC2D2A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity.	Bachmann-Gagescu R	Journal of medical genetics	2015	PMID: 26092869
CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype-phenotype correlation.	Mougou-Zerelli S	Human mutation	2009	PMID: 19777577
Mutation spectrum of Meckel syndrome genes: one group of syndromes or several distinct groups?	Tallila J	Human mutation	2009	PMID: 19466712

Text-mined citations for rs386833752 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated May 09, 2026